Teaching An Old Drug New Tricks: Repositioning Strategies for Spinal Muscular atrophy

Figures & data

Table 1. Status of SMN-dependent drugs in clinical trials for spinal muscular atrophy.

ClinicalTrials.gov ID	Therapeutic	Activity	Current status (as of May 2019)
NCT02268552	Branaplam™	Oral small-molecule stabilizer of U1-snRNP complex and SMN2 pre-mRNA to promote higher expression of full-length SMN2 mRNA	Phase II trials
NCT03779334	Risdiplam™	Oral small-molecule promoter of full length SMN2 mRNA via splicing modification	Phase II trials
NCT02122952	Zolgensma™	Gene therapy delivery of exogenous SMN1 via adeno-associated virus effector to promote higher SMN abundance	Phase I trials
NCT02240355	R06885247	Oral small-molecule splicing modulator of SMN2 pre-mRNA to promote higher expression of full length SMN2 mRNA	Terminated

Figure 1. Targets for survival motor neuron-independent drug repositioning strategies for spinal muscular atrophy.

Overview of pathological molecular effectors or biological pathways (in red) that could be therapeutically modulated by commercially available drugs (in blue) to treat CNS, NMJ and skeletal muscle pathologies in spinal muscular atrophy.

NMJ: Neuromuscular junction.

Figure 2. Proposed experimental model for drug repositioning strategies.

Proteomic and transcriptomic approaches can be used to define the differential expression patterns of genes, proteins and biological pathways between diseased and healthy states. Published literature or integrated publicly available drug databases allow for the uncovering of commercially available drugs that can restore the aberrant molecular profiles in the diseased state. The drugs then require to first be validated for safety and efficacy in relevant in vitro and in vivo models. Successful drug candidates can then be evaluated in clinical trials, with Phase I usually bypassed as information regarding safety and dosages are known. Finally, the drug is approved for patient use if it demonstrates benefits in clinical trials.